シンポジウム

シンポジウム Unraveling the CA2 circuit in the hippocampal function

3S5-1 AGE-DEPENDENT SPECIFIC CHANGES IN AREA CA2 OF THE HIPPOCAMPUS AND SOCIAL MEMORY DEFICIT IN THE 22Q11.2 MOUSE MODEL OF SCHIZOPHRENIA Chevaleyre Vivien¹，Piskorowski Rebecca¹，Diamantopoulou Anastasia^2,4，Siegelbaum Steven³，Nasrallah Kaoutsar¹，Mukai Jun²，Gogos Joseph² ¹Centre National Research Scientifique, Unite Mixte Research 8118, University Paris，²Department of Physiology and Cellular Biophysics, Department of Neuroscience and Pharmacology, College of Physicians and Surgeons, Columbia University，³Howard Hughes Medical Institute, Department of Neuroscience and Pharmacology, College of Physicians and Surgeons, Columbia University，⁴Department of Psychiatry, College of Physicians and Surgeons, Columbia University An imbalance between excitation and inhibition is observed in several pathologies. Post-mortem studies have shown a reduction in interneuron number in hippocampal area CA2 with schizophrenia. We examined transmission in area CA2 of Df（16）A+/- mice, a mouse model of the 22q11.2 deletion syndrome, which presents the highest known risk for developing schizophrenia. These mice recapitulate many of the behavioral deficits and neuroanatomical changes observed in humans. We found that Df（16）A+/- mice have fewer Parvalbumin-expressing interneurons in area CA2, with no differences found in areas CA1 and CA3. Second, we found that the level of feed-forward inhibitory transmission is also reduced in area CA2 of these mice. As a consequence, excitatory transmission from Schaffer collaterals is larger in basal conditions. Third, these differences did not manifest until the mice reached adulthood. Fourth, we also found an age-dependent hyperpolarization of the resting membrane potential of CA2 pyramidal cells in Df（16）A+/- mice. CA2 pyramidal cells in Df（16）A+/- mice displayed fewer action potentials in response to proximal and distal excitatory input stimulation. Long-term depression at inhibitory synapses is reduced in Df（16）A+/- mice, resulting in impaired action potential firing in Df（16）A+/- mice. Finally, Df（16）A+/- mice display a deficit in social memory, a phenotype similar to the one observed after complete silencing of CA2 pyramidal neurons. Thus, our results shed new light onto a potential mechanism underlying the social memory impairment observed during schizophrenia.		3S5-2 Pioneer discovery of the CA2 function in the hippocampus Sekino Yuko Division of Pharmacology, National Institute of Health Sciences Among subregions of the Cornu Ammonis (CA1/CA2/CA3) in the hippocampus, the CA2 region has remained unexplored in detail for long time, although a huge amount of studies have been performed on the CA3, CA1 and CA3-CA1 synapses. In early 1990’s, the optical device with sufficiently high resolution for time and spatial information has been developed. The device enabled us to observe spread of depolarization along the CA3-CA2-CA1 pathway in the rat hippocampal slices, suggesting the distinguishable function of the CA2 (Sekino, et al 1997). This report is the first description of CA2 activity in the hippocampus. Additionally we have immnohistochemically shown that adenosine A1 receptors are highly expressed in the CA2 neurons (Ochiishi, et al 1999). Inputs from the suprammamillary nucleus, which provides the classical definition of the CA2, is involved in the spread of epileptic activity in the hippocampus (Saji, et al 2000). We have also shown that number of C-Fos expressed neurons in the CA2 of rats placed in the open field is reduced (unpublished data). These studies have added much information on the cytoarchitectural information of the CA2 by Lorente de Nov (1934), but further precise functional roles of the CA2 have not been elucidated until recent technical break through, the discovery of the genetic molecular markers defining the CA2 neurons. I will introduce our pioneer discovery and insights of the CA2 function.

3S5-3 An examination of the local circuitry and impact on network activity by supramammillary nucleus inputs to area CA2 of the hippocampus Piskorowski Rebecca，Robert Vincent，Therreau Ludivine，Chevaleyre Vivien Centre National Research Scientifique, Unite Mixte Research 8118, University Paris Area CA2 of the hippocampus differs from areas CA1 and CA3 in many aspects. Recent findings indicate that this region is unlikely to code spatial information, but is critical for social memory. Neurons in area CA2 form a reciprocal connection with the supramammillary nucleus（SuM）, a hypothalamic structure activated by stress and reward. We are using targeted viral vectors in combination with transgenic mouse lines in order to selectively express channelrhodopsin in SuM neurons and selectively excite projections from these neurons in transverse hippocampal slices. We have found that SuM fibers form excitatory synapses onto both pyramidal cells and interneurons in the deep portion of the somatic layer in area CA2. An inhibitory post-synaptic potential is evoked in CA2 pyramidal cells following SuM stimulation, which is entirely abolished after blocking excitatory transmission. These results reveal that SuM fiber stimulation effectively evokes action potentials in interneurons that feed-forward onto CA2 pyramidal cells. In contrast, the direct glutamatergic transmission between SuM and CA2 pyramidal cells is quite weak and unable to evoke firing. Furthermore, SuM activity results in the release of neuropeptide, allowing for an indirect modulation of inhibitory transmission in this area. We are examining the properties and axonal projections of the interneurons that receive inputs from SuM fibers in order to better understand how SuM activity alters the local circuitry in the hippocampus. We postulate that strong recruitment and modulation of perisomatic inhibition in this area may influence network oscillatory activity.		3S5-4 The role of CA2 in regulating information flow in the hippocampus McHugh Thomas J. RIKEN Brain Science Institute Understanding the flow and processing of spatial and contextual information across the subregions（CA1/CA2/CA3/DG）of the hippocampus has been a long standing goal of neuroscience and has provided key insights to the formation, consolidation and expression of declarative memory. Key to this understanding has been the combination of in vivo recording of the spatially selective place cells and local field potential oscillations across the structure with modern genetic tools that allow interventions in neuronal function at specific nodes of the circuit. While this approach has yielded insights into the contributions of CA1, CA3 and the DG, the role of the small, yet highly connected CA2 region to spatial processing and circuit function remain largely unexplored. CA2 is unique in its pattern of synaptic plasticity and its anatomy, possessing multiple bidirectional connections with areas both within and outside the hippocampus, including layer II of the entorhinal cortex, CA3, the supramammillary nucleus of the hypothalamus, and the medial septum. Using in vivo recordings in awake behaving mice we have found that while many aspects of CA2 physiology are similar to the neighboring CA3 region, the consequences of CA2 silencing are quite unique. Using multiple genetically encoded systems we have investigated the consequences of both transient and chronic silencing of CA2 synaptic transmission on hippocampal physiology. Surprisingly, our data suggests that CA2 may serve a crucial role as a regulator of interhippocampal information flow.